IAEA/WHO guideline on good manufacturing practices for ...
Transcript of IAEA/WHO guideline on good manufacturing practices for ...
Working document QAS/21.878/Rev1 July 2021
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DRAFT WORKING DOCUMENT FOR COMMENTS: 2
3
IAEA/WHO guideline on good 4
manufacturing practices for investigational 5
radiopharmaceutical products 6
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Please send your comments to Dr Herbert Schmidt, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Sinéad Jones ([email protected]) before 17 September 2021. Please use the “Table of Comments” for this purpose.
Our working documents are sent out electronically and are also placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy-standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link. If you wish to receive all our draft guidelines, please send your email address to [email protected] and your name will be added to our electronic mailing list.
9 10 © World Health Organization 2021 11 12 All rights reserved. 13 14 This is a draft. The content of this document is not final, and the text may be subject to revisions before publication. The 15 document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or 16 in whole, in any form or by any means without the permission of the World Health Organization. 17 18 Please send any request for permission to: Sinéad Jones, Norms and Standards for Pharmaceuticals, Technical Standards and 19 Specifications, Department of Health Products Policy and Standards, World Health Organization, CH-1211 Geneva 27, 20 Switzerland, email: [email protected]. 21 22 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 23 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 24 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 25 border lines for which there may not yet be full agreement. 26 27 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 28 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 29 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 30 31 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 32 33 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility 34 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable 35 for damages arising from its use. 36 37 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 38
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Working document QAS/21.878/Rev1 Page 2
SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/21.878: 40
IAEA/WHO guideline on good manufacturing practices 41
for investigational radiopharmaceutical products 42
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Description of Activity Date
Following a recommendation by the Fifty-fifth Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP), the WHO Secretariat was recommended to revise the existing guideline on good manufacturing practices (GMP) for investigational products.
October 2020
Preparation of first draft working document. The GMP guidelines for Investigational radiopharmaceutical products is prepared in alignment with the revised document on GMP for Investigational products QAS/20.863 by an International Atomic Energy Agency (IAEA) expert working group.
January-February 2021
Mailing of working document to the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations (EAP) inviting comments and posting of the working document on the WHO website for public consultation.
March 2021
Consolidation of comments received and review of feedback. Preparation of working document for discussion.
May 2021
Discussion of the feedback received on the working document in a virtual meeting with an IAEA expert working group.
June 2021
Preparation of revision 1 of the working document for next round of public consultation.
July 2021
Mailing of revision 1 of the working document inviting comments, including to the EAP, and posting the working document on the WHO website for a second round of public consultation.
July - September2021
Consolidation of comments received and review of feedback. Preparation of working document for discussion.
September 2021
Discussion of the feedback received on the working document in a virtual meeting with an IAEA expert working group.
September-October 2021
Presentation to the Fifty-sixth meeting of the ECSPP. TBD
Any other follow-up action as required.
Working document QAS/21.878/Rev1 Page 3
IAEA/WHO guideline on good 45
manufacturing practices for 46
investigational radiopharmaceutical 47
products 48
49
50
Background 51
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In view of a rapidly expanding field of molecular imaging and targeted radiopharmaceutical therapy, 53
combined with the absence of a dedicated guidance specific to the manufacture of investigational 54
radiopharmaceuticals used in both early and late clinical trials, the World Health Organization (WHO), 55
in partnership with the International Atomic Energy Agency (IAEA), has raised the urgency for the 56
generation of a new IAEA/WHO guideline on good manufacturing practices for investigational 57
radiopharmaceutical products . 58
59
The objective of this guideline is to meet current expectations and trends in good manufacturing 60
practices (GMP) specific to investigational radiopharmaceuticals used in clinical trials (i.e. Phase I, Phase 61
II and Phase III trials) and to harmonize the text with the principles from other related international 62
guidelines. 63
64
This text was developed in alignment with the Good manufacturing practices; supplementary guidelines 65
for the manufacture of investigational pharmaceutical products for clinical trials in humans (1). 66
67
1. Introduction 68
2. Scope 69
3. Glossary 70
4. Quality management 71
5. Quality risk management 72
6. Personnel 73
7. Documentation 74
• Specifications 75
• Manufacturing formulae and processing instructions 76
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• Batch manufacturing records 77
8. Premises 78
9. Equipment and utilities 79
10. Materials 80
• Starting materials 81
• Reference standards for analytical purposes 82
11. Production 83
• Manufacturing operations 84
• Packaging and labelling 85
12. Quality control 86
13. Qualification and validation 87
14. Complaints 88
15. Recalls 89
16. Returns 90
17. Shipping 91
18. Destruction 92
93
Abbreviations 94
References 95
Further reading 96
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1. Introduction 97
98
1.1. Radiopharmaceuticals are rapidly re-emerging as clinically valuable tools used in the 99
diagnosis and treatment of various types of disease. Molecular imaging agents offer 100
unparalleled methodology to not only help elucidate the presence and the extent of 101
disease but also to help characterize the disease, select specific patients for a particular 102
therapy or to evaluate a treatment response. Additionally, novel targeted radioligand 103
therapies offer alternatives to patients for whom no other treatment options exist. 104
105
1.2. This rapid expansion is accompanied by a set of challenges due to the complexity and 106
unique nature of these agents. One of the main challenges associated with novel 107
radiopharmaceutical development is how to define the proper balance with respect to the 108
investigational radiopharmaceuticals manufacturing controls required when conducting 109
early clinical studies, and the subsequent implementation of additional controls as the 110
radiopharmaceutical is developed further into pivotal Phase III trials. Having inadequate 111
manufacturing controls during early clinical evaluations either carries the risks of 112
unnecessary patient harm or jeopardizes the validity of the collected study results. On the 113
other hand, redundant manufacturing controls, particularly in the initial stages of 114
development, carry the risk of slowing the pace of clinical development of potentially life-115
saving therapies. This risk is further intensified by other factors such as the high costs and 116
lengthy time associated with the actual clinical conduction of the study, the completion of 117
the pre-clinical evaluation of the agent, and the low probability of successful marketing 118
approval. In light of these challenges, a balanced approach with respect to manufacturing 119
process controls is essential as the degree of manufacturing process controls is correlated 120
to the particular stage of radiopharmaceutical development, the nature of the agent itself, 121
and the clinical study goals. 122
123
1.3. This guidance provides recommendations on the minimum standards that should be in 124
place when preparing novel radiopharmaceuticals for Phases I-III clinical investigations that 125
do not have a marketing authorization. 126
127
1.4. Investigational radiopharmaceuticals are used for testing purposes, as a reference in a clinical 128
trial for an unauthorized indication and to gain further information about the authorized form. 129
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1.5. Depending on the country, these products are sometimes not covered by legal and 130
regulatory provisions in the areas of good manufacturing practices (GMP). The lack of both 131
high-level GMP requirements and prior knowledge of the risk of contamination and cross-132
contamination of products contribute to the risk of using them in human subjects. In 133
addition, the risk may be further enhanced in cases of incomplete knowledge of the potency, 134
human biodistribution, and toxicity of the investigational radiopharmaceuticals. 135
136
1.6. To minimize the risks and to ensure that the results of clinical trials are unaffected by 137
inadequate safety, quality or efficacy arising from unsatisfactory production, investigational 138
radiopharmaceuticals should be produced and managed in accordance with an effective quality 139
management system (QMS) and the recommendations contained in this guideline. 140
141
1.7. Procedures should be flexible to allow for changes whenever necessary, through properly 142
controlled and traceable change management system as knowledge of the process increases 143
in accordance with the stages of development of the product. 144
145
1.8 Investigational radiopharmaceuticals should be produced in a manner that is compliant to 146
GMP requirements that are specific to the particular stage of agent development. 147
148
1.9 As the clinical development of radiopharmaceutical progresses from Phases I-II to the 149
pivotal Phase III and commercial stage, additional manufacturing process controls and 150
analytical method validation should be implemented so as to ensure: 151
• that subjects of clinical trials will be protected from poor quality products due to 152
unsatisfactory manufacturing; 153
• that consistency exists between and within batches of the investigational 154
radiopharmaceuticals; and 155
• that consistency exists between the investigational product and the future 156
commercial product. 157
158
1.10 The selection of an appropriate dosage form for clinical trials is important. While it is 159
accepted that the dosage form in early trials may be different from the anticipated final 160
formulation (e.g. different buffers, radiostabilizers and other excipients), in the pivotal 161
Phase III studies, it should be equivalent to the projected commercial presentation in terms 162
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of the expected biodistribution profile. If there are significant differences between the 163
investigational and commercial dosage forms, data should be submitted to the registration 164
authorities to demonstrate that the final dosage form is equivalent, in terms of biodistribution 165
and stability, to that used in the clinical trials. 166
167
1.11 The quality of investigational radiopharmaceuticals should be appropriate for the particular 168
stage of development. For example, it should be feasible to apply only the critical 169
manufacturing controls for agents in Phase I and Phase II trials, while the manufacture of 170
investigational radiopharmaceuticals for Phase III clinical studies should generally have the 171
same degree of applied controls as for commercial manufactured products. 172
173
1.12 This document should be read in conjunction with other World Health Organization (WHO) 174
GMP guidelines, including good clinical practices (GCP), good documentation practices and 175
International Atomic Energy Agency (IAEA) radiation protection documents related to 176
radiopharmaceuticals (2-8). 177
178
2. Scope 179
180
2.1 The recommendations in this guideline are applicable to investigational radiopharmaceutical 181
products for human use. 182
183
2.2 The recommendations of this guideline do not apply to radiopharmaceuticals in Phase IV (with 184
marketing authorization) that already have regulatory authority approval for a certain 185
indication but might be used to conduct a clinical study for a different indication. In those 186
situations, the IAEA/WHO guideline on GMP for radiopharmaceutical products should be used 187
(2). 188
189
3. Glossary 190
191
The definitions given below apply to the terms used in this guideline. They may have different 192
meanings in other contexts. 193
194
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active pharmaceutical ingredient (API). With respect to radiopharmaceutical preparations, the API is 195
the radioactive molecule that is responsible for the radiopharmaceutical mechanism of action. This API 196
may be in the form of the radionuclide by itself, if its use by itself is clinically indicated, or in the form 197
of radionuclide coupled to a non-radioactive ligand or vector molecule. 198
199
“as low as reasonably achievable” (ALARA). Used to define the principle of underlying optimization of 200
radiation protection. This is practised based on the principles of time, distance and shielding, as well 201
as an emphasis on creating adequate awareness among all stakeholders. 202
203
clinical trial. Any systematic study on (radio)pharmaceutical products in human subjects, whether in 204
patients or other volunteers, in order to discover or verify the effects of, and/or identify any adverse 205
reaction to, investigational products and/or to study the absorption, distribution, metabolism and 206
excretion of the products with the object of ascertaining their efficacy and safety. 207
208
Clinical trials are generally divided into Phases I-IV, although Phase IV studies usually do not apply to 209
investigational radiopharmaceuticals and, thus, are not mentioned further. It is not always possible to 210
draw clear distinctions between these phases and different opinions about details and methodology do 211
exist. However, the individual phases, based on their purposes as related to the clinical development 212
of pharmaceutical products, can be briefly defined as follows: 213
➢ Phase I. These are the first trials for new radiopharmaceuticals (also called “first in human”), 214
often carried out in healthy volunteers. Their purpose is to make a preliminary evaluation of 215
safety, and an initial pharmacokinetic/pharmacodynamic profile, an initial safety assessment 216
of the active ingredient and radiation dosimetry. 217
➢ Phase II. The purpose of these studies is to determine activity and to assess the short-term 218
safety. The trials are performed in a limited number of subjects, but higher than Phase I, and 219
are also aimed to determine optimal administered dose. In case of therapeutic 220
radiopharmaceuticals, they are also aimed to the clarification of dose-response relationships 221
in order to provide an optimal background for the design of extensive therapeutic trials. 222
➢ Phase III. This phase involves trials in large (and possibly varied) patient groups for the purpose 223
of determining the short- and long-term safety-efficacy, and assessing its overall and relative 224
diagnostic accuracy and therapeutic value of the intended radiopharmaceutical. Phase III 225
studies are often multicentric. The pattern and profile of any frequent adverse reaction 226
must be investigated and special features of the product must be explored (e.g. clinically 227
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relevant drug interactions, factors leading to differences in effect, such as age, etc.). In 228
general, the conditions under which the trials are conducted should be as close as possible 229
to the normal conditions of use. 230
231
finished pharmaceutical product (FPP). With respect to radiopharmaceutical preparations, the finished 232
pharmaceutical product is a combination of the active pharmaceutical ingredient and other 233
components of the formulation such as diluents, radioprotectants and other formulation excipients. In 234
some instances, the active pharmaceutical ingredientis co-produced concurrently with the finished 235
pharmaceutical product in a single seamless process. In other cases, the radioactive active 236
pharmaceutical ingredient is synthesized first and then is fomulated further as a separate process to 237
yield the finished pharmaceutical product. In all cases, the finished pharmaceutical product is created 238
once the active pharmaceutical ingredient is formulated in the final formulation form. 239
240
good manufacturing practices for radiopharmaceutical products. Good manufacturing practices (GMP) 241
for radiopharmaceutical products are a set of practices, using a traceable process, that ensure that 242
radiopharmaceutical products are consistently produced and controlled to the quality standards 243
appropriate for their intended use and designed to consistently yield the radiopharmaceutical product. 244
GMP fall under the umbrella of the overall quality management system (QMS). 245
246
investigational radiopharmaceutical. Any radiopharmaceutical product (new compound or a 247
commercial product) being evaluated in a clinical trial. 248
249
investigator. The person responsible for the trial and for protecting the rights, health and welfare 250
of the subjects in the trial. The investigator must be an appropriately qualified person, legally 251
allowed to practice medicine/dentistry. 252
253
manufacturing or production. For the purpose of this document, this term is defined in the same 254
way as in the WHO guideline on good manufacturing practices (GMP) for radiopharmaceuticals 255
(3). These terms refer to all the operations performed leading up to the finished pharmaceutical 256
product, including the purchase of starting materials, production, quality control (QC), release and 257
storage of radiopharmaceuticals. 258
259
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monitor. A person appointed by, and responsible to the sponsor for monitoring and reporting the 260
progress of the trial and for the verification of data. 261
262
order. An instruction to process, package and/or ship a certain number of doses of an 263
investigational radiopharmaceutical. 264
265
preparation or kit-reconstitution. For the purpose of this document, these terms are defined in the 266
same way as in the WHO guideline on good manufacturing practices (GMP) for 267
radiopharmaceuticals (3). These terms refer to all the procedures carried out as per instructions from 268
marketing authorization holders which involves addition of radionuclide solution approved by 269
regulatory authorities to an approved cold kit. 270
271
product specification file(s). Reference file(s) containing all the information necessary to draft the 272
detailed written instructions on processing, packaging, labelling, quality control testing, batch 273
release, storage conditions and shipping. 274
275
protocol. A document which gives the background, rationale and objectives of the trial and describes· 276
its design, methodology and organization, including statistical considerations and the conditions under 277
which it is to be performed and managed. It should be dated and signed by the investigator/institution 278
involved and the sponsor, and can, in addition, function as a contract. 279
280
radiopharmaceutical product. For the purpose of this document, this term is defined in the same 281
way as in the WHO guideline on good manufacturing practices (GMP) for radiopharmaceuticals 282
(3), such as, any pharmaceutical product that, when ready for use, contains one or more radionuclides 283
(radioactive isotopes) included for medicinal purposes. 284
285
retention sample. An additional sample of the final drug product that is collected and stored for the 286
purposes of being analysed, should the need arise. 287
288
sponsor. An individual, company, institution or organization which takes responsibility for the 289
initiation, management and/or financing of a clinical trial. When an investigator independently 290
initiates and takes full responsibility for a trial, the investigator also then assumes the role of the 291
sponsor. 292
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4. Quality management 293
294
4.1 There should be a comprehensively designed, clearly defined, documented and correctly 295
implemented QMS in place. Senior management should assume the responsibility for this, as 296
well as for the quality of the investigational product. 297
298
4.2 All parts of the QMS should be adequately resourced and maintained. 299
300
4.3 The QMS should incorporate GMP which would be applied to all the life cycle stages of the 301
products, including the transfer of technology and the interface between the manufacture and 302
the trial site (e.g. shipment, storage, labelling). 303
304
4.4 The QMS should ensure that: 305
• products are designed and developed in accordance with the requirements of this 306
document and other associated guidelines, such as good clinical practices (GCP), good 307
laboratory practices (GLP) and good storage and distribution practices (GSDP), where 308
appropriate (3-5); 309
• responsibilities are clearly specified in job descriptions; 310
• operations are clearly specified in a written form; 311
• arrangements are made for the manufacture, supply and use of the correct starting 312
and packaging materials; 313
• all necessary controls on starting materials, intermediate products, bulk products and 314
other in-process controls are in place; 315
• calibrations and validations are carried out where necessary; 316
• the finished pharmaceutical product is correctly processed and quality controlled 317
according to the defined procedures; 318
• deviations and changes are investigated and recorded with an appropriate level of root 319
cause analysis done and appropriate corrective actions and/or preventive actions 320
(CAPA) identified and taken. For the manufacture of Phase I and II radiopharmaceutical 321
investigational products, the information on deviations, manufacturing process 322
changes, investigations and corrective actions may be captured in a documentation 323
system that is less regimented than the structured CAPA, Deviation, out-of-324
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specification (OOS), and Change Control standard operating procedures (SOPs) and 325
forms that are normally used during manufacture of commercial radiopharmaceutical 326
products where the degree of variability and reliability of the process has been 327
established and validated. This less regimented documentation system allows for 328
manufacturer flexibility that is essential for the manufacturing of the novel agent , as 329
this process is inherently subject to a higher degree of variability when compared to 330
agents in later stages of pharmaceutical development. Regardless of the 331
documentation system utilized, the relevant information must be adequately captured 332
and be traceable. 333
• there is an appropriate system for quality risk management; and 334
• satisfactory arrangements exist to ensure, as far as possible, that the investigational 335
radiopharmaceuticals are stored, distributed and subsequently handled so that their 336
quality is maintained. 337
338
5. Quality risk management 339
340
5.1 A quality risk management system (QRM) should cover a systematic process for the 341
assessment, control, communication and review of risks to the quality of the product and, 342
ultimately, to the protection of the trial subjects and patients (6). Specific areas of quality risk 343
assessment should include: 344
- sterility assurance; 345
- expiration time; 346
- method of sterilization; 347
- mass of the drug substance or ligand; 348
- physicochemical properties of the radionuclide/radopharmaceutical; 349
- planned dosing schedule (i.e. single dose or multiple doses into the same study 350
subject); 351
- route of administration; 352
- agent specific in-vitro stability; and 353
- the degree of clinical investigator supervision. 354
355
5.2 The QRM should ensure that: 356
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• the evaluation of the risk is based on scientific knowledge and experience with the 357
process and product, and should be ultimately linked to the the protection of the 358
patient; 359
• as the agent development continues, the basis of risk assessment should be the 360
transition from scientific knowledge and experience to process validation; 361
• procedures and records for QRM are retained; and 362
• the level of effort, formality and documentation of the QRM process is commensurate 363
with the level of risk. 364
365
5.3 QRM should be applied both proactively and retrospectively, when appropriate. 366
367
6. Personnel 368
369
6.1 There should be a sufficient number of appropriately qualified personnel available to carry out 370
all the tasks for which the manufacturer of investigational products is responsible. 371
372
6.2 Individual responsibilities should be clearly defined, recorded as written descriptions and 373
understood by all persons concerned. 374
375
6.3 A designated person, with experience in product development and clinical trial processes, and 376
relevant GMP/GCP guidelines, should ensure that there are systems in place that meet the 377
requirements of this guideline and other relevant GMP guidelines. 378
379
6.4 Personnel involved in the development, production and quality control of investigational 380
products should be appropriately trained in relevant GMP and in the requirements specific to 381
the manufacture of investigational radiopharmaceuticals. 382
383
6.5 Production and quality control operations should be carried out under the control of 384
clearly identified responsible persons who are separately designated and independent, 385
one from the other. 386
387
6.6 In the manufacture of investigational radiopharmaceuticals, the same operator may be 388
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qualified either as a production operator or quality control operator, or both, and the 389
training for a specific function should be documented.Normally, the same operator should 390
not perform both manufacture and quality control testing of the same batch of 391
investigational radiopharmaceuticals. In circumstances where this may not be possible (e.g. 392
radiopharmacies infrequently manufacturing investigational radiopharmaceuticals for Phase I-393
II clinical evaluations), the same trained operator may perform both production and quality 394
control testing, but it must be ensured that the batch release is performed by another 395
independent person. 396
397
6.7 In the manufacture of investigational radiopharmaceuticals, it may be possible for an the 398
expertly qualified person responsible for batch release to also participate in either the batch 399
production or quality control of a particular batch of investigational radiopharmaceutical. 400
However, if this qualified person does participate in either production or quality control testing 401
of the particular batch, he or she cannot be responsible for the release of this batch of 402
investigational radiopharmaceutical.. 403
404
7. Documentation 405
406
7.1 Good documentation is an essential part of a QMS. The documents should be appropriately 407
designed, prepared, reviewed and distributed. They should also be appropriate for their 408
intended use. 409
410
7.2 The documents should be approved, signed and dated by the appropriate responsible 411
person(s). No authorized document should be changed without the prior authorization and 412
approval of the responsible person(s). 413
414
7.3 The documentation requirements applied during the manufacture of Phases I-II investigational 415
radiopharmaceuticals may be less vigorous than the documentation requirements applied 416
during the manufacture of Phase III investigational radiopharmaceuticals, but they would still 417
need to be adequate in order to allow for traceability of the manufacturing process. 418
419
420
421
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Specifications 422
423
7.4 Specifications (for starting materials, primary packaging materials, intermediate, bulk and 424
finished products), batch formulae and production instructions should be as precisely detailed 425
as possible and should take into account the latest state of the art. 426
427
7.5 In developing specifications, attention should be paid to the characteristics which may 428
affect the efficacy and safety of products, namely: 429
• sterility and bacterial endotoxins; 430
• radioactive strength; 431
• radiochemical purity; 432
• specific activity, if applicable; 433
• the batch size that is intended for the trial, where applicable; 434
• the in-use stability; 435
• the preliminary storage conditions; 436
• the shelf life of the product; 437
• the appearance of the finished pharmaceutical product; 438
• the radionuclidic purity, if applicable; and 439
• chemical purity, if applicable. 440
441
7.6 As a result of the development of an investigational radiopharmaceutical, specifications may 442
be changed by following a documented procedure. Changes should be authorized by a 443
responsible person. Each new version should take into account the latest data and 444
information, current technology, and regulatory and pharmacopoeia requirements. There 445
should be traceability to the previous version(s). The reasons for any change should be 446
recorded. The impact of the change on any on-going clinical trial, product quality, stability, bio-447
availability and bio equivalence (where applicable) should be considered. 448
449
7.7 Information necessary to prepare the intended investigational radiopharmaceutical should 450
be summarized in a product specification file, which contains reference to the relevant 451
documentation (e.g. SOPs, qualification/validation protocols, analytical methods, stability 452
data, storage and shipment conditions, etc.) required to perform processing, packaging, 453
quality control testing, batch release, labelling, storage conditions and/or shipping of the 454
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desired product. 455
456
7.8 The product specification file should indicate who has been designated or trained as the 457
designated responsible person(s) for the release of batches. 458
459
7.9 The product specification file(s) should be continuously updated whilst, at the same time, 460
ensuring the appropriate traceability to the previous version(s). 461
462
Manufacturing formulae and processing instructions 463
464
7.10 Detailed manufacturing formulae, processing and packaging instructions and records should 465
be available. Where this is not possible, other clear, written instructions and written records 466
should be available for every manufacturing operation or supply. 467
468
7.11 These records should be used when preparing the final version of the documents to be 469
used in routine manufacture. 470
471
7.12 Batch records should be retained for at least five years after the termination or discontinuance 472
of the clinical trial or after the approval of the investigational radiopharmaceutical. 473
474
7.13 Where the data are intended for inclusion in an application for marketing authorization 475
purposes, the records should be maintained until the end of the life cycle of the product. 476
477
Batch manufacturing records 478
479
7.14 Processing, packaging and testing records should be kept in sufficient detail for the sequence 480
of operations to be accurately traced. They should contain any relevant remarks which 481
increase the existing knowledge of the product, allow and reflect changes and improvements 482
in the manufacturing operations, and justify the procedures used. 483
484
8. Premises 485
486
8.1 The premises, where investigational radiopharmaceutical products are manufactured, should be 487
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located, designed, constructed and maintained to suit the operations to be carried out. The design 488
of the laboratories used for the handling of radioactive materials should always consider the need 489
for radiation protection, ALARA compliance, and exhibit a high level of cleanliness and controls to 490
minimize possible microbial contamination (7-9). 491
492
8.2 Because of the potentially high radiotoxicity of some long-lived, high potency products (e.g. 493
alpha-emitters), radioactive decontamination and active monitoring are of particular 494
importance. Effective radiation containment procedures should be followed in order to 495
prevent contamination of the operators. 496
497
8.3 In case the same facility and equipment are used to prepare different radiopharmaceuticals, 498
including investigational radiopharmaceuticals, the layout and design of premises should aim to 499
minimize the risk of errors and mix-ups and permit effective cleaning and maintenance in order to 500
avoid contamination, cross-contamination and, in general, any adverse effect on the quality of the 501
products. 502
503
8.4 General technical requirements for the premises involved in the routine production of 504
radiopharmaceuticals also apply in case of investigational radiopharmaceuticals. For instance, 505
drains should be avoided wherever possible and should not be present in clean rooms. Where drains 506
are required, these should be appropriately designed; sinks should be excluded from clean areas; 507
technical area (e.g. rooms to access the rear of hot cells) access points should be configured in a 508
way to minimize the entrance of the maintenance and technical personnel to the production (clean) 509
areas. 510
511
8.5 The heating, ventilation and air-conditioning (HVAC) system and pressure cascade design for the 512
different areas should be appropriately designed and maintained to minimize the risk of product 513
contamination, and to protect the personnel from risks of radiation exposure. The pressure 514
differentials for areas of the facility, where the relative pressure differentials need to be maintained 515
(e.g. cleanrooms where the quality of air is controlled), should be monitored (11). 516
517
8.6 The facility must be equipped with appropriate radiation monitoring systems suitable for routine 518
radioactive contamination monitoring for both areas and operators. 519
520
8.7 The appropriate controls should be in place to promote containment of radioactive gases and 521
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vapours. The premises must be equipped with appropriate radioactive gas emission monitoring 522
system. 523
524
8.8 Radioactive gases should be removed through separate air handling units fitted with the appropriate 525
filters before being exhausted. These should be regularly checked for performance. The 526
recirculation of potentially radiation contaminated air should not be allowed. 527
528
8.9 A dedicated area and dedicated equipment should be used for the manufacture of any 529
investigational radiopharmaceutical product involving human blood or plasma. 530
531
8.10 Quality control laboratories should be segregated from production areas. 532
533
8.11 The premises must be equipped with appropriately designed radioactive decontamination areas 534
where operator decontamination may be carried out in compliance with approved protocols. At a 535
minimum, these areas should be equipped with hand washing and eye washing stations. 536
537
8.12 The facility must be equipped with appropriately designed radioactive waste storage areas. 538
539
9. Equipment and utilities 540
541
9.1 Equipment and utilities should be selected, located, constructed and maintained to suit the 542
operations to be carried out. 543
544
9.2 Equipment and utilities should be qualified for their intended use. This may include user 545
requirement specifications, design qualification (if applicable), installation qualification (IQ), 546
operational qualification (OQ) and performance qualification (PQ). Equipment and devices, as 547
appropriate, should be calibrated and maintained. 548
549
9.3 Equipment maintenance, qualification and calibration operations should be recorded and 550
records maintained. 551
552
9.4 Computerized systems, such as those controlling equipment, should be verified to ensure they 553
are reliable and fit for the intended purpose (10). 554
Working document QAS/21.878/Rev1 Page 19
9.5 The dose calibrator (also known as the activity meter) should be qualified using suitable 555
reference standards. If such a reference standard recognized by a national authority is not 556
available, dose calibrator manufacturer recommendations or published literature may be used 557
when deciding upon the appropriate dial setting. 558
559
10. Materials 560
561
Starting materials 562
563
10.1 The consistency of the production of investigational radiopharmaceutical products may be 564
influenced by the quality of the starting materials. Their physical, chemical and, when 565
appropriate, microbiological properties should therefore be defined, documented in their 566
specifications, and controlled. 567
568
10.2 Specifications for precursors for radiolabelling should be as comprehensive as possible, given 569
the current state of knowledge. They should include, for example, identity, purity or 570
certification of origin (if applicable) and any other parameter or characteristic required to make 571
the material suitable for its intended use. 572
573
10.3 Detailed information on the quality of precursors for radiolabelling and excipients (as well as of 574
packaging materials) should be available. 575
576
10.4 Starting materials should be accepted by performing in-house testing. During the manufacture 577
of investigational radiopharmaceuticals for Phase I-II clinical trials, the in-house testing may 578
also be in the form of a review of the Certificate of Analysis (CoA) supplied by the reliable 579
material supplier, to confirm compliance with the specification set by the investigational agent 580
manufacturer. For positron emission tomography (PET) radiopharmaceuticals, the materials 581
acceptance based on CoA review may also apply to the Phase III stage, as long as the final 582
product release testing adequately confirms that materials are of correct quality were used. 583
For the manufacture of cold kit products, generators and therapeutic radiopharmaceuticals in 584
Phase III stages, additional physical tests (e.g. material identity confirmation) may need to be 585
performed by the radiopharmaceutical manufacturer as part of material acceptance process, 586
in addition to CoA review. 587
Working document QAS/21.878/Rev1 Page 20
Reference standards for analytical purposes 588
589
10.5 Reference standards from reputable sources (e.g. qualified vendors) should be used, if 590
available. 591
592
10.6 If not available from any source, the reference substance(s) for the precursor for radiolabelling 593
should be prepared, tested and released as reference material(s) by the producer of the 594
investigational pharmaceutical product. 595
596
11. Production 597
598
11.1 Investigational radiopharmaceuticals intended for use in clinical trials should be 599
manufactured at a facility that is specified in the investigational agent regulatory 600
application. 601
602
11.2 Where activities are outsourced to contract facilities, the contract must then clearly state, 603
inter alia, the responsibilities of each party, compliance with GMP or this guideline, and 604
that the product(s) to be manufactured or controlled are intended for use in clinical trials. 605
Close cooperation between the contracting parties is essential. 606
607
11.3 Access to restricted areas should be by authorized and trained personnel only. 608
609
11.4 Processes should be designed to minimize the risk of contamination, cross-contaminations and 610
mix-ups. The following measures may be adopted to minimize these risks: 611
(a) procedures for clearing the room of previous product materials; 612
(b) processing and filling in segregated areas; 613
(c) avoiding the manufacture of different products at the same time, either in the same 614
dedicated space or by the same personnel; 615
(d) performing manufacturing area decontamination and visual pre-checks; 616
(e) using manufacturing “closed systems” (e.g. automated systems), whenever possible; 617
and 618
(f) using pre-assembled kit (cassettes), whenever possible. 619
620
Working document QAS/21.878/Rev1 Page 21
11.5 The stability and shelf life of the finished product should be defined following the execution of 621
a suitable written protocol. 622
623
11.6 The expiration dates and times for radiopharmaceuticals should be based on the results of an 624
adequate number of stability studies. 625
626
Manufacturing operations 627
628
11.7 As process knowledge of an investigational radiopharmaceutical is often not comparable 629
with that of a radiopharmaceutical used for standard clinical care, process validation may 630
not always be complete during the development phase of products; thus, critical quality 631
attributes, process parameters and in-process controls should be identified, based on risk 632
management principles and experience with analogous products, if available. 633
634
11.8 The necessary instructions for production should be defined and may be adapted based 635
on the experience gained during radiopharmaceutical development itself. 636
637
11.9 For sterile investigational products, the controls to assure sterility of the final drug product 638
should be no less than for licensed products (9). However, sterility verification studies (i.e. 639
bacteristasis/fungistasis) may not need to be conducted prior to pivotal Phase III studies. 640
641
Packaging and labelling 642
643
11.10 At least the following information should be listed on the primary packaging container label: 644
(a) name of the product and batch number; 645
(b) name of the manufacturer; 646
(c) route of administration; 647
(d) amount of activity at calibration date and time in appropriate units; 648
(e) volume; 649
(f) where relevant, the international symbol for radioactivity; 650
(g) cautionary statements (e.g. “For clinical investigational use only”); and 651
(h) the study or trial number. 652
653
Note: Reporting information about activity (“strength”) on the primary label may not always be 654
Working document QAS/21.878/Rev1 Page 22
possible due to radiation protection reasons. In this case, the information may be reported on 655
the secondary packaging label. 656
657
11.11 In the absence of regulatory authority requirements, the following minimum information may 658
be listed on the secondary packaging container label, in addition to any information listed on 659
the primary packaging: 660
(a) the finished pharmaceutical product formulation composition; 661
(b) excipient information; 662
(d) storage instructions; 663
(e) the address of the manufacturer, study sponsor, or investigator, as appropriate; 664
(f) radioactive concentration at calibration date and time, if applicable; 665
(g) end-of-synthesis date and time; 666
(h) expiration date and time; and 667
(i) specific activity or mass. 668
669
11.12 The packaging must ensure that the investigational product remains in good condition during 670
transport and storage. Any opening of, or tampering with, the outer packaging during 671
transport should be readily discernible. 672
673
12. Quality control 674
675
12.1 Quality control should cover the sampling and testing of both the starting materials and the 676
radiopharmaceutical final drug products, ensuring that materials are not released for use until 677
their quality has been determined to conform to the predefined acceptance specifications. 678
679
12.2 As processes may not be standardised or fully validated, testing takes on more importance in 680
ensuring that each batch meets the approved specification at the time of testing. 681
682
12.3 The release of a batch of an investigational radiopharmaceutical product should only occur 683
after the designated responsible person has certified that the product meets the relevant batch 684
release requirements. At a minimum, these requirements should include the following: 685
• a review and approval of batch records, including control reports, in-process test 686
reports, changes, deviations and release reports demonstrating compliance with the 687
Working document QAS/21.878/Rev1 Page 23
product specification file, the order and protocol; 688
• verification of appropriate production conditions; 689
• verification of the quality of starting materials (status of approval, CoA, etc.); 690
• verification of the validation status of facilities, equipment, processes and methods, as 691
appropriate; and 692
• verification of conditions of storage and shipment, if applicable. 693
• verification of successful completion of quality control tests required for batch release. 694
695
12.4 Due to the inherent rapid radioactive decay of radiopharmaceuticals containing radionuclides 696
with relatively short half-lives, these products may be released and administered prior to 697
completion of all quality control testing. Under these circumstances, the required pre-release 698
and post-release testing should be clearly defined and documented. 699
700
12.5 Sampling procedures should consider the nature and the characteristics of the material being 701
sampled (e.g. a small batch size and/or its radioactive content) to make sure that the samples 702
are representative of the entire batch of radiopharmaceutical. 703
704
12.6 Quality control samples should be prepared, handled and stored in a way to ensure the 705
adequate identification and segregation of the test samples to avoid mix-ups and cross-706
contamination. 707
708
12.7 In the event when a finished pharmaceutical product batch fails to meet a release acceptance 709
specification (i.e. an OOS event occurs), an investigation should be conducted and 710
documented. During the investigation, the affected batch should be segregated. If the 711
investigation confirms the OOS result, the finished pharmaceutical product should be rejected. 712
A confirmed OOS that is detected during post-release testing, but before the product has been 713
administered to the patient/volunteer, requires an immediate notification to the end-user. A 714
batch of finished pharmaceutical product involved in an OOS event may be released only if (1) 715
the investigation reveals a clear evidence that the obtained result is invalid, and (2) 716
confirmatory testing results confirm the absence of non-compliance to the acceptance 717
specifications. 718
719
12.8 Retention samples from every batch of a particular investigational radiopharmaceutical 720
Working document QAS/21.878/Rev1 Page 24
product should only be collected if they can be used to obtain meaningful testing data in 721
the future. However, the collection of the retention samples is not required. The duration 722
of storage of retention samples should be based on the ability to collect valid test data 723
from using the sample. 724
725
13. Qualification and validation 726
727
13.1 The extent of qualification and validation activities should be in accordance with a risk-based 728
approach, considering the complexity and critical aspects of the intended radiopharmaceutical 729
production. 730
731
13.2 The extent of qualification and validation required for the manufacture of investigational 732
radiopharmaceuticals in Phases I-II trials may be less than for the manufacture of 733
investigational radiopharmaceuticals in pivotal Phase III trials. Nevertheless, the critical 734
characteristics of the investigational radiopharmaceutical should always be addressed. For 735
example, critical manufacturing step in-process control parameters such as reaction 736
temperatures and/or transfer of the activities, may need to be defined and monitored at any 737
stage of development; on the other hand, the validation of less critical controls such as 738
bioburden sample collection or determination of maximum in-process holding times, may not 739
be required during the Phases I-II. 740
741
13.3 The facilities and equipment need to be properly maintained and calibrated at any stage of 742
development. 743
744
13.4 Equipment should be qualified for its intended use. At a minimum, the equipment should be 745
verified to have conformance to the equipment manufacturer preventative maintenance (PM) 746
and OQ requirements, as well as investigational radiopharmaceutical manufacturer PQ 747
requirements, as applicable. 748
749
13.5 The validation of aseptic investigational radiopharmaceutical production procedures presents 750
special problems, as the batch size is often very small and the number of units filled may be not 751
adequate for a full validation protocol. Thus, the validation of aseptic procedures needs to be 752
supported by an operator and process validation via media fill test, which consists of conducting 753
Working document QAS/21.878/Rev1 Page 25
a process simulation using broad spectrum bacterial growth media to demonstrate that the 754
aseptic processing/controls and production environment are capable of producing a sterile 755
product. The successful completion of media fill testing is a prerequisite for the clinical 756
production of investigational radiopharmaceuticals at any stage of development. 757
758
13.6 Manufacturing process validation should only be carried out after all of the critical 759
requirements (e.g. media fill testing, relevant standard operating procedures {SOP} for 760
operator training, and equipment PM and OQ) have been completed. The validation batches 761
campaign should include an adequate number of batches of the intended 762
radiopharmaceutical(s). The number of batches and the batch size range should be 763
predetermined as part of a risk assessment performed prior to process validation. In general, 764
the completion of a minimum of three consecutive batches aimed for validation and stability 765
studies is sufficient for the purposes of completing manufacturing process validation in Phase I 766
trials. However, the number of batches produced may need to be increased in certain 767
situations. For example, more validation and stability runs may be required when the 768
manufacturer is trying to qualify multiple suppliers of a particular critical component (e.g. 769
radionuclide provided by multiple suppliers). 770
771
13.7 Defined, documented and reproducible analytical methods aimed to establish chemical, 772
radiochemical and radionuclidic purity, as well as identity, specific activity (if applicable) and 773
impurities content, should be established before any manufacture for human subjects begins. 774
However, analytical method validation protocols fully compliant with the International Council 775
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 776
standards (12) for validation may be generated and implemented as part of transition into 777
pivotal Phase III trials. 778
779
13.8 Compendial analytical methods applied by the investigational radiopharmaceutical 780
manufacturer that are described in relevant pharmacopeia do not require validation but may 781
require verification prior to the initiation of manufacture for pivotal Phase III trials. For 782
example, the compendial endotoxin testing method may not require full analytical method 783
validation as described in relevant ICH guidances but may require the verification via 784
conduction of finished pharmaceutical product specific inhibition/enhancement studies. 785
786
13.9 General principles on validation of analytical procedures may be followed (12), however, the 787
Working document QAS/21.878/Rev1 Page 26
unique nature of radioactivity should be considered and specific adaptations should be made, 788
where required. 789
790
14. Complaints 791
792
14.1 There should be a written procedure describing the management of complaints. The 793
procedure should provide a clear and concise description of responsibilities, actions that may 794
need to be undertaken, communication pathways and structure, traceability and reporting 795
requirements in the event a complaint is received. 796
797
14.2 Any complaint concerning a product defect should be recorded with all the original details and 798
thoroughly investigated. 799
800
14.3 Where necessary, the appropriate follow-up action, possibly including product recall, should 801
be taken after the investigation and evaluation of the complaint. 802
803
14.4 All decisions made and measures taken as a result of a complaint should be recorded and 804
referenced to the corresponding batch records. 805
806
14.5 Any potential impact on the trial and/or on the product development should be 807
investigated in order to determine the cause and to take any necessary corrective action. 808
809
15. Recalls 810
811
15.1 There should be a written procedure describing the managing of a recall of an investigational 812
radiopharmaceutical. The procedure should provide a clear and concise description of 813
responsibilities, actions that may need to be undertaken, communication pathways and 814
structure, traceability and reporting requirements in the event a product recall is initiated. 815
816
15.2 The recall of a product should be documented and inventory records should be kept. 817
818
15.3 Multiple project-specific and product recall procedures may need to be implemented for 819
Working document QAS/21.878/Rev1 Page 27
various radiopharmaceuticals in order to reflect the requirements for a specific project. 820
For example, the product recall requirements for a manufacturer that supplies 821
investigational agents to the clinic within the same institution or hospital may differ 822
significantly from the manufacturer that works with a pharmaceutical company sponsor 823
and distributes the manufactured product to multiple external clinics. In all cases, the 824
exact requirements need to be clearly defined and the staff need to be trained on those 825
specific requirements. 826
827
16. Returns 828
829
16.1 Investigational radiopharmaceuticals should be returned under the agreed conditions 830
defined by the sponsor, specified in written procedures and approved by authorized staff 831
members. 832
833
16.2 Return processes should be in accordance with the handling of radioactivity and radiation 834
protection rules. 835
836
16.3 Inventory records of returned products should be kept. 837
838
16.4 Returned radiopharmaceuticals should not be reused. 839
840
16.5 Since the return of radioactive products is often not practical, the main purpose of recall 841
procedures for radiopharmaceutical products should be to prevent their use rather than an 842
actual return. If necessary, the return of radioactive products should be carried out in 843
accordance with national, and where applicable, international transport regulations (13). 844
845
17. Shipping 846
847
17.1 The shipping of investigational radiopharmaceuticals should be carried out in accordance 848
with written procedures laid down in the protocol or shipping order given by the sponsor. 849
850
17.2 Shipping processes should also be in accordance with international and local rules (13). 851
Working document QAS/21.878/Rev1 Page 28
852
17.3 The shipment should be accompanied by a printed form, including the relevant 853
information related to the investigational radiopharmaceutical (e.g. the same information 854
included in the secondary packaging label). 855
856
18. Destruction 857
858
18.1 The activity of the active principle of investigational radiopharmaceuticals decreases 859
following the decay law and half-life of the radionuclide; thus, usually there is no need for 860
product destruction. 861
862
18.2 Should the product be destroyed, however, international and local rules on handling 863
radioactivity and radiation protection should be followed. A dated certificate of, or receipt 864
for, destruction should be provided to the sponsor. These documents should clearly identify, 865
or allow traceability to the batches and/or patient numbers involved and the actual quantities 866
destroyed. 867
868
Abbreviations 869
870
API active pharmaceutical ingredient 871
CAPA corrective actions and/or preventive actions 872
CoA certificate of analysis 873
GCP good clinical practices 874
GLP good laboratory practices 875
GMP good manufacturing practices 876
GSDP good storage and distribution practices 877
HVAC heating, ventilation and air conditioning 878
IQ installation qualification 879
OQ operational qualification 880
PQ performance qualification 881
PM preventative maintenance 882
QMS quality management system 883
Working document QAS/21.878/Rev1 Page 29
QRM quality risk management (system) 884
SOP standard operating procedure 885
886
References 887
888
1. WHO good manufacturing practices for investigational pharmaceutical products for clinical 889
trials in humans. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: 890
thirty-fourth report. Geneva: World Health Organization; 1996: Annex 7 (WHO Technical 891
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standards/guidelines/production/trs863-annex7-who-gmp-investigational-893
pharmaceutical-products-clinical-trials-humans.pdf?sfvrsn=2432f236_0, accessed 4 894
November 2020). 895
Update in process: WHO Working Document QAS/20.863 (https://www.who.int/docs/default-896
source/medicines/norms-and-standards/current-projects/qas20-863-gmp-for-investigational-897
products.pdf?sfvrsn=3993da76_2, accessed 26 February 2021). 898
2. IAEA/WHO guideline on good manufacturing practices for radiopharmaceutical products. In: 899
WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-fourth report. 900
Geneva: World Health Organization; 2020: Annex 2 (WHO Technical Report Series, No. 1025 901
(https://www.who.int/docs/default-source/medicines/norms-and-902
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3. WHO handbook for good clinical research practices, 2002; 905
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research and development, TDR/PRD/GLP/01.2, 2001; 909
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https://www.who.int/publications/m/item/trs-1025-annex-7-gdp-medical-products, accessed 915
4 November 2020). 916
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Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013: 918
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10. WHO good manufacturing practices: guidelines on validation. Appendix 5. Validation of 938
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954
Further reading 955
956
• International Ethical Guidelines for Health-related Research Involving Humans Prepared by the 957
Council for International Organizations of Medical Sciences (CIOMS) in collaboration with the 958
World Health Organization (WHO), Geneva, 2016 (https://cioms.ch/wp-959
content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf, accessed 4 November 960
2020). 961
• The International Pharmacopoeia. Geneva, World Health Organization; updated regularly 962
(https://www.who.int/medicines/publications/pharmacopoeia/en/ and https://apps.who.int/ 963
phint/2019/index.html#p/home, accessed 1 May 2020). 964
• EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines, EU Commission 965
Directives 91/356/EEC, as amended by Directive 2003/94/EC, and 91/412/EEC 966
(https://ec.europa.eu/health/documents/eudralex/vol-4_fr, accessed 4 November 2020). 967
• WHO good manufacturing practices for pharmaceutical products: main principles. In: WHO 968
Expert Committee on Specifications for Pharmaceutical Preparations: forty-eight report. 969
Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986 970
https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex2.971
pdf?ua=1 accessed 4 November 2020). 972
973
*** 974